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Uderzo was born in Fismes (Marne, France), to parents, Silvio (of Venetian descent) and Iria Crestini (of Tuscan descent), who had recently immigrated from La Spezia, Italy.[2] His childhood ambitions were to become an aircraft mechanic, despite his talents in art becoming apparent at an early age.

Uderzo obtained French citizenship in 1934, and during World War II, the teenaged Uderzo left Paris and spent a year in Brittany, where he worked on a farm and helped with his father's furniture business. He loved Brittany, both for its scenery and its people. In fact, many years later, when the time came to choose a location for Asterix's village, Goscinny left the decision entirely to Uderzo, only stipulating that it should be near the sea in case the characters needed to travel by boat. Uderzo had no hesitation in choosing Brittany.

Uderzo began a successful career as an artist in Paris after the war in 1945, with creations such as Flamberge and also Clopinard, a small one-legged old man who triumphs against the odds. From 1947 to 1948 he created some other comics, such as Belloy and Arys Buck.

Throughout some more creations and travelling for the next few years, he eventually met René Goscinny in 1951. The two men quickly became good friends, and decided to work together in 1952 at the newly opened Paris office of the Belgian company, World Press. Their first creations were the characters Oumpah-pah, Jehan Pistolet and Luc Junior.[3][4] In 1958 they adapted Oumpah-pah for serial publication in the Franco-Belgian comics magazine Tintin, though it ran only until 1962.[5] In 1959 Goscinny and Uderzo became editor and artistic director (respectively) of Pilote magazine, a new venture aimed at older children. The magazine's first issue introduced Astérix to the French world, and it was an instant hit.[3][6] During this period Uderzo also collaborated with Jean-Michel Charlier on the realistic series Michel Tanguy, later named Les Aventures de Tanguy et Laverdure.[3]

Astérix was serialised in Pilote, but in 1961 the first album Astérix le gaulois (Asterix the Gaul) was published as an individual album. By 1967, the comic had become so popular that both decided to completely dedicate their time to the series. After Goscinny's death in 1977, Uderzo continued to write and illustrate the books on his own, though at a significantly slower pace (averaging one album every three to five years compared to two albums a year when working with Goscinny). The cover credits still read "Goscinny and Uderzo".

Uderzo married Ada Milani in 1953 and has one daughter Sylvie Uderzo (b. 1956). According to The Book of Asterix the Gaul, it was speculated that Uderzo had based the characters Panacea and Zaza on Ada and Sylvie respectively, though this has been denied by Uderzo. When Uderzo sold his share of Editions Albert René to Hachette Livre, Sylvie accused him in a column in Le Monde, that with this action it was "as if the gates of the Gaulish village had been thrown open to the Roman Empire". Sylvie owns 40% of Editions Albert René, while the remaining 60%, previously owned by Uderzo and by Goscinny's daughter, is currently owned by Hachette Livre.[7]

According to the UNESCO's Index Translationum, Uderzo is the 10th most often translated French language author (Goscinny being 4th) and the third most often translated French language comics author behind René Goscinny and Hergé.[9]